The Molecular Basis For The Initiation Of Squamous Differentiation And How It Is Disrupted In Oral Cancers
Funder
National Health and Medical Research Council
Funding Amount
$64,631.00
Summary
Squamous cancers of the mouth, nose and throat occur due to defects in the cells that line these regions. We have shown that a major defect is that the lining cells are unable to stop growing and mature into cells that provide a barrier against the environment. In this proposal we will undertake studies to identify why these cancers cells do not mature properly. In doing so we will be able to identify new strategies that may be used to treat patients with this frequently deadly cancer.
Osteosarcoma is the most common cancer of bone. It osurs most frequently in childhood (teenage years) and current therapy is limited to surgery and chemotherapy. We have developed a new model of osteosarcoma that displays a high degree of similarity to human osteosarcoma. We aim to further understand this model and apply these findings to help treat human osteosarcoma.
Development Of A Novel Therapy For The Treatment Of Epidermal Squamous Cell Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Squamous cell carcinomas (SCC) are the most common life-threatening form of skin cancer in Australia. SCCs commonly arise in areas of the body that have been exposed to excessive amounts of UV irradiation. The cells of the skin from which SCCs are derived are called keratinocytes. UV irradiation causes lesions within these cells such that their growth and maturation are disrupted leading to deregulated growth and maturation and hence tumour formation. We have previously identified a protein, E2F ....Squamous cell carcinomas (SCC) are the most common life-threatening form of skin cancer in Australia. SCCs commonly arise in areas of the body that have been exposed to excessive amounts of UV irradiation. The cells of the skin from which SCCs are derived are called keratinocytes. UV irradiation causes lesions within these cells such that their growth and maturation are disrupted leading to deregulated growth and maturation and hence tumour formation. We have previously identified a protein, E2F, that is central to this process and whose inhibition leads to decreased cancer cell growth. During the course of these studies we noted that the deregulation of E2F could also lead to the disruption of keratinocyte maturation. This led us to propose that the inhibition of E2F in SCCs may result in both decreased cancer cell growth as well as the reinstatement of a normal maturation process. this would make E2F inhibitors a very attractive therapeutic for treating SCC. In the present study we aim to explore the ability and the mechanism by which E2F modulates keratinocyte proliferation and maturation. This will be done in vitro as well as in animal models of SCC. These studies will be required in order to take the E2F inhibitors into clinical trials.Read moreRead less
Roles Of Impaired Apoptosis And Differentiation In Tumourigenesis And Therapy
Funder
National Health and Medical Research Council
Funding Amount
$21,656,910.00
Summary
The ten scientific laboratories in this program have joined forces to investigate two ways in which tumours develop. Both are of particular interest, because they suggest new ways in which cancer might be overcome. Most of our tissues are continually renewed throughout life by production of new cells. Therefore many of the old cells in each tissue must die off to maintain the proper cell numbers. To eliminate cells that are no longer needed or have become damaged, the body has developed a remark ....The ten scientific laboratories in this program have joined forces to investigate two ways in which tumours develop. Both are of particular interest, because they suggest new ways in which cancer might be overcome. Most of our tissues are continually renewed throughout life by production of new cells. Therefore many of the old cells in each tissue must die off to maintain the proper cell numbers. To eliminate cells that are no longer needed or have become damaged, the body has developed a remarkable cell suicide process termed apoptosis. Unfortunately, however, occasionally a random accident to the genes in one of our cells prevents the machinery for apoptosis from being turned on. In that case, the cell will not die when it should and, by continually dividing, it may eventually give rise to a cancer. Since most cancer cells still retain most of the machinery for apoptosis, however, a drug that could switch on this natural cell death machinery would provide a promising new approach to cancer therapy. Identifying and developing such drugs is one major long-term goal of this program. The other focus of our program concerns stem cells. These are rare cells with the remarkable ability to generate an entire tissue. For example, one of our laboratories has identified stem cells that can generate all the cells in the breast. The almost unlimited regenerative capacity of stem cells has a built-in danger. If a stem cell acquires the ability to proliferate excessively, it can go on to form a tumour. Indeed, many cancer researchers now suspect that rare stem cells within a tumour cause its inexorable growth. If tumour growth is maintained by stem cells, it will be essential to develop new forms of therapy that target these rare cancer stem cells rather than merely the bulk of the tumour cells. This is another key long-term goal of our program.Read moreRead less
Synthetic Analogues Of The Actinomycin, Quinamycin And Nogalamycin Groups Of Antitumour Antibiotics
Funder
National Health and Medical Research Council
Funding Amount
$376,433.00
Summary
The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar ....The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar scenario in the treatment of adults with leakaemias and non-Hodgkins lymphomas. The underlying cause of drug resistance is the genetic instability of cancer cells which results in tumours that are heterogeneous, making it almost inevitable that a cancer cell will arise that is resistant to treatment. There are many mechanisms of resistance, some of which are peculiar to particular drug types, some are permeability barriers and some involve genetic deregulation of the biochemistry of cell death. One way of subverting resistance is by the use of drugs whose mechanism of action is novel so that the tumour is challenged to devise a new defense. Here, we are attempting to develop synthetic analogues of a class of naturally- occurring antitumour antibiotic whose mechanism of action is unusual but which has not been exploited by medicinal chemists because of the difficulty of the chemistry involved. These antibiotics work by binding to DNA and inhibiting the first step in the process whereby genes are turned into proteins. We have designed compounds that are chemically accessible that our preliminary work suggests mimic the DNA-binding and biological properties of the natural antibiotics. The proposed work will enable us to evaluate whether this new class of agent has experimental antitumour activity, particularly amongst drug-resistant tumours.Read moreRead less